Of the six major tropical diseases (filariasis, schistosomiasis, malaria, leishmaniasis, trypanosomiasis and leprosy) recognized by WHO as the main cause of morbidity, mortality and poor socio-economic growth in the tropics, filariasis is one of the most widespread and debilitating diseases of humans.
Filariasis is a helminthic infection caused by a number of slender and thread-like nematodes which invade blood circulation, lymphatics, lymph nodes, connective and subcutaneous tissues, peritoneal cavities and other parts of the human body.
The disease is transmitted to man by a large variety of hematophagous arthropods, often mosquitoes and flies, which introduce a large number of infective larvae in blood circulation while feeding on the human blood. The female worms produce microfilariae which make their way to blood circulation and subcutaneous tissues from where they are taken up by a suitable insect vector. On reaching the insect's body, the microfilariae (first stage larvae, Li larvae) undergo several moultings to form infective larvae (L3 larvae) which reach the blood circulation of the definite host through the bites of the insect. Soon the infective larvae enter into lymphatic system and connective tissues where they slowly mature into adult male and female worms. The male and female adult mate to produce microfilariae which find their way to peripheral blood circulation.
It is estimated that nearly 300 to 400 million people around the world are infected with different forms of filariasis and many more are living at the risk of acquiring such infections.
The clinical manifestations of lymphatic filariasis are characterized by three phases:
(1) Inflammatory, leading to high fever, chills, vomiting, malaise, enlargement of lymph nodes, pain and swelling in the testes and thickening of spermatic cord. PA0 (2) Obstructive, causing blockade of the lymphatic circulation which slowly leads to hydrocele and chyluria. PA0 (3) Elephantiasis, marked by massive enlargement of legs, arms, scrotum and breasts. PA0 wherein A is ##STR2## PA0 wherein R.sup.1 and R.sup.2 independently are furanyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl or triazolyl wherein each aromatic ring is optionally substituted with one, two or three substituents selected from --NR.sup.8 R.sup.9, C.sub.1-8 -alkylthio, C.sub.1-6 -alkoxy, azido, cyano, halogen, hydroxy, C.sub.1-6 -alkyl, nitro, mercapto or trifluoromethyl; and PA0 X is --CH.sub.2 --, --O-- or --N(R.sup.3)-- wherein R.sup.3 is hydrogen or C.sub.1-6 -alkyl; and PA0 R.sup.4 is hydrogen or C.sub.1-6 -alkyl; and PA0 m is 1 or 2; and PA0 n is 1 when m is 1 and n is 0 when m is 2; and PA0 R.sup.5 and R.sup.6 each represents hydrogen or may when m is 2 together represent a bond; and PA0 R.sup.7 is hydroxy or C.sub.1-6 -alkoxy; and PA0 R.sup.8 and R.sup.9 independently are hydrogen or C.sub.1-6 -alkyl; and PA0 p is 0, 1, 2 or 3; and PA0 q is 0, 1 or 2; and PA0 r is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. PA0 +++=Rapid coiling and uncoiling (normal movement) PA0 ++=Significant slowing down of movement PA0 +=Microfilariae mostly elongated, but with occasional twitching PA0 0=No movement (microfilariae dead)
The early stage of onchocerciasis (river blindness) is marked by skin rash and persistent pruritis (onchodermatitis) followed by pachydermia over thighs and buttocks. Later the patient may develop pain in the eyes, photophobia, lacrimation and edema of eyelids which slowly leads to chronic conjuctivitis; finally the patient loses vision. River blindness thus poses a serious problem in many parts of the African continent causing loss of vision and blindness due to damage of cornea, iris and pupil by entrance of microfilariae into the eyeball of a large number of patients every year.
In recent years much pharmacological research concerning y-aminobutyric acid (hereinafter designated GABA), an inhibitory neurotransmitter in the mammalian central nervous system, has been carried out. As a result, much interest has been focused on the various potential pharmacological approaches to the enhancement of GABA'ergic function in humans, for example, by the direct agonism on GABA receptors, the inhibition of enzymatic breakdown of GABA, or by the inhibition of the uptake of GABA into neuronal and glial cell bodies. Recently, the discovery of high levels of GABA in microfilariae suggested the existence of GABA receptors in such organisms, thereby creating a new field of interest in filariae therapeutics by GABA'ergic compounds (J. Pharm. Pharmacol. 1989, 41, 191). It has been shown that filariae are sensitive (paralysis or death) to high concentrations of GABA inside the parasite. However, the passage of GABA through the parasite cuticle is poor due to its relatively polar nature excluding this compound as a therapeutic. The obvious modification by preparation of the more lipophilic prodrug esters of GABA has been investigated (J. Pharm. Pharmacol. 1989, 41, 191). A different approach to enhancement of GABA'ergic function inside the parasite is the embodiment of this invention where compounds known as lipophilic GABA uptake inhibitors now has been shown to exhibit paralysis and death of such parasites. Furthermore, the compounds of the invention has been found to be orally active.